Treatment of idiopathic inflammatory myopathies Anthony A. Amato a and Robert C. Griggs b

Transcription

1 Treatment of idiopathic inflammatory myopathies Anthony A. Amato a and Robert C. Griggs b Purpose of review This article reviews the results of recent therapeutic trials in dermatomyositis, polymyositis, and inclusion body myositis and suggests an approach to treating patients with inflammatory myopathy. Recent findings We reviewed 10 double-blind, placebo-controlled therapeutic trials in patients with inflammatory myopathy. Only one, using intravenous immunoglobulin in refractory dermatomyositis, indicated benefit. A brief trial of azathioprine in polymyositis and eight studies using various treatments in inclusion body myositis did not show benefit. Summary There have been no adequate double-blind, placebo-controlled therapeutic trials of dermatomyositis and polymyositis. It is generally accepted, however, that these disorders respond to immunosuppressive agents. Prednisone is usually the initial treatment. There is no agreement on how prednisone should be administered and even less agreement about other agents. Inclusion body myositis, which now appears to be the most common (in adults), is unresponsive to immunosuppressive and immunomodulating therapies. There are candidate treatments for inclusion body myositis and a need for additional doubleblind, placebo-controlled therapeutic trials in all patients with inflammatory myopathy. Keywords dermatomyositis, polymyositis, inclusion body myositis, inflammatory myopathy, myositis, treatment Curr Opin Neurol 16: # 2003 Lippincott Williams & Wilkins. a Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, and b Department of Neurology, Strong Memorial Hospital, University of Rochester School of Medicine, Rochester, New York, USA Correspondence to Anthony A. Amato MD, Department of Neurology, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA Tel: ; fax: ; aamato@partners.org Current Opinion in Neurology 2003, 16: Abbreviations CBC complete blood count GGT g-glutamyl transpeptidase IBM inclusion body myositis IVIG intravenous immunoglobulin # 2003 Lippincott Williams & Wilkins Introduction Dermatomyositis, polymyositis, and inclusion body myositis (IBM) are the three major categories of idiopathic inflammatory myopathy and they are clinically, histologically, and pathogenically distinct [1 6,7. ]. Dermatomyositis is a humorally mediated microangiopathy, while polymyositis is a T-cell mediated disorder in which there is attack on muscle fibers. The pathogenesis of IBM is unknown. Dermatomyositis and polymyositis are considered to be responsive to immunosuppressive and immunomodulating therapies, in contrast to IBM, which is refractory to all treatment. There have been a number of therapeutic studies and recent review articles on the inflammatory myopathies [1,7.,8. ]. It is difficult to draw any firm conclusions regarding efficacy of various treatments because of inadequate study designs (1) grouping adult and childhood dermatomyositis together with polymyositis and IBM patients; (2) not using controls, prospective, blind designs; and (3) using poor endpoints such as subjective improvement, decreasing creatine kinase levels rather than objective improvement in muscle strength and function [9,10]. There have now been 10 prospective, double-blinded, placebo-controlled trials in the treatment of inflammatory myopathy, most within the past decade (Table 1) [11 17,18..,19.. ]. Seven of these studies involved IBM all of which were negative. Only one study, intravenous immunoglobulin in dermatomyositis [11], demonstrated efficacy of treatment. Nevertheless, specialists experienced in treating patients with inflammatory myopathy believe that various modes of immunotherapy are helpful in dermatomyositis and polymyositis [1,3,7.,8. ]. In contrast, IBM is generally refractory to immunosuppressive and immunomodulating therapies [2,3,5,6,7.,20]. Specific therapies In the subsequent sections we review the immunosuppressive and immunomodulating agents that have been used to treat myositis and outline an approach to treating these disorders. In general, we use many of the agents discussed below in patients with dermatomyositis and polymyositis, but do not recommend treating IBM with immunosuppressive or immunomodulating agents. Corticosteroids Retrospective studies have demonstrated that high-dose prednisone reduces morbidity and improves muscle strength and function [1,2,9,21]. Short courses of intravenous solumedrol (1 g daily for 3 days) is also DOI: /01.wco

2 570 Neuromuscular diseases: muscle Table 1. Prospective, double-blind, placebo-controlled trials in inflammatory myopathies Study Type of myositis Study drug Efficacious (yes/no) Dalakas et al. (1993) [11] DM IVIG Yes Bunch et al. (1980) [12] PM Azathioprine No Miller et al. (1992) [13] No DM and PM Plasma exchange and leukopheresis Dalakas et al. (1997) [14] IBM IVIG No Walter et al. (2000) [15] IBM IVIG No Dalakas et al. (2001) [16] IBM IVIG a No Muscle Study Group (2001) IBM Avonex No [17] Rutkove et al. (2002) [18.. ] IBM Oxandrolone No Badsrising et al. (2002) IBM Methotrexate No [19.. ] Muscle Study Group (in preparation) IBM Avonex No DM, dermatomyositis; IVIG, intravenous immunoglobulin; PM, polymyositis; IBM, inclusion body myositis. a Patients were also receiving prednisone. beneficial [22]. Prednisone is the usual initial treatment. Solumedrol is indicated for patients with severe generalized weakness or those with life-threatening systemic complications (e.g. interstitial lung disease, myocarditis). Between 58 and 100% of dermatomyositis patients have at least a partial response; 30 66% return to normal strength with prednisone alone [2,9]. For polymyositis over 80% improve; 10 33% return to normal [2,9]. Improvement typically is noted within 3 6 months of starting prednisone. When no response is noted after an adequate trial of high-dose prednisone, other alternative diagnoses (e.g. IBM or an inflammatory muscular dystrophy) should be considered and further diagnostic evaluation considered. IBM is generally not responsive to prednisone or other immunosuppressive or immunomodulating therapies [1,2,5,20,23]. Retrospective, unblinded studies reported mild or transient improvement in IBM treated with prednisone [9,10]. Often subjective improvement or lower serum creatine kinase levels on prednisone was defined as a benefit. However, since prednisone with or without other immunosuppressive agents may decrease serum creatine kinase levels and may even reduce inflammatory cell infiltrates on repeat muscle biopsies [23], objective clinical endpoints based on muscle strength and function are needed. These have not been shown to improve. Moreover, in natural history studies of IBM, 50% of untreated patients remain stable and 25% of patients appear to improve over a 6-month period of follow up [24]. We initiate prednisone at a high dose ( mg/kg/day up to 100 mg every day) as a one time dose in the morning in patients with dermatomyositis and polymyositis. After 2 4 weeks of daily prednisone, we usually switch directly to alternate day dosing (i.e. 100 mg on alternate days). Patients with more severe disease may need to be slowly tapered to alternate day dosing over 2 3 months (decrease by 10 mg/week on alternate days) [3]. Approximately 5 10% of patients cannot be managed on alternate day prednisone and need daily dosing. In addition, patients with diabetes mellitus will usually require daily prednisone given wide fluctuations in their serum glucose on alternate day dosing. In such diabetic cases, after an initial 2 weeks of prednisone mg/kg/ day, they receive mg/kg/day (e.g. 50 mg/day). We follow patients initially at least every 2 4 weeks and maintain the high-dose prednisone until patients are back to normal strength or until improvement in strength has reached a plateau (usually 4 6 months). Subsequently, we slowly taper the prednisone by 5 mg every 2 3 weeks. Once the dose is reduced to 20 mg on alternate days, we taper prednisone no faster than 2.5 mg every 2 3 weeks. If the patient does not show objective improvement after 4 6 months of prednisone, or if there is an exacerbation during the taper, we add a second-line agent: methotrexate, azathioprine, mycophenolate or intravenous immunoglobulin (IVIG). At the same time, the prednisone dose is doubled and given daily (no more than 100 mg/day) for at least 2 weeks before switching back to alternate day dosing. Once a patient has regained their strength, we resume the prednisone taper at a slower rate. The majority of adult patients must remain on prednisone or other immunosuppressive/immunomodulating therapies. Nevertheless, we attempt to taper patients completely off these medications since myositis is occasionally a monophasic illness. Although it is important to monitor the serum creatine kinase levels, adjustments of prednisone and other immunosuppressive agents should be based on the objective clinical examination and not the creatine kinase levels or the patient s subjective response. Serum creatine kinase levels can be elevated in patients with no objective weakness or normal or only mildly elevated in patients with active disease. An increasing serum creatine kinase can serve as a warning of a relapse. Unless there is objective clinical deterioration in strength, we do not increase the dose of the immunosuppressive agent. In such instances, however, the dose should not be decreased until it is certain that the patient is stable. Some patients become weaker during long-term corticosteroid treatment. In such cases a relapse of the myositis needs to be distinguished from steroid myopathy. High-

3 Idiopathic inflammatory myopathies Amato and Griggs 571 dose, long-term steroids and lack of physical activity invariably cause type 2 muscle fiber atrophy. Remarkably, in patients with active myositis corticosteroids seldom cause major proximal muscle weakness. A flare of the underlying myositis should be considered in patients who become weaker during prednisone taper, have increasing serum creatine kinase levels, and abnormal spontaneous activity on electromyography. In contrast, once the disease has been controlled, patients with normal serum creatine kinase and electromyograph and other evidence of corticosteroid toxicity (e.g. Cushingoid appearance) are more likely to have steroid myopathy. Careful use of physical therapy, maintaining physical activity, and using the minimum dose of corticosteroids will prevent muscle wasting. Concurrent management We measure bone density with dual energy X-ray absorptiometry at baseline and every 6 months while patients are receiving corticosteroids. A bone density less than 2.5 standard deviations below normal indicates osteopenia. In patients with osteopenia, we start a bisphosphonate (e.g. alendronate 70 mg/week orally) [25]. In postmenopausal women without osteoporosis we prophylactically start alendronate 35 mg/week orally. In premenopausal women and men, prophylactic treatment is initiated if there is some degree of bone loss (Tscores between 1.0 and 2.5 SD). In all patients we prescribe calcium supplementation (1 g/day) and vitamin D ( IU/day). We do not prophylactically treat with histamine-h 2 receptor blockers, unless the patient develops gastrointestinal discomfort or has a history of peptic ulcer disease. We recommend patients take Tums (two tablets 3 4 times/day) as they are useful both as an antacid and a source of calcium. Patients are instructed to start a lowsodium, low-carbohydrate, high-protein diet and counseled to prevent excessive weight gain. In addition, we prescribe physical therapy and an aerobic exercise program. Physical activity and exercise help reduce bone loss and prevent type 2 muscle fiber atrophy. Blood pressure is measured on each visit along with periodic eye examinations for cataracts and glaucoma. Fasting blood glucose and serum potassium levels are monitored. Potassium supplementation may be required if the patient becomes hypokalemic. Second-line therapies We start a second-line agent in patients poorly responsive to prednisone or in those who relapse during prednisone taper (Table 2). In addition, we begin treatment with a second-line agent at the same time we initiate corticosteroids in patients with severe weakness or life-threatening systemic complications (e.g. interstitial lung disease, myocarditis). A second-line agent is also started along with prednisone in postmenopausal women and men over 50 with bone loss on their dual energy X-ray absorptiometry for their potential corticosteroid-sparing effect. Methotrexate In retrospective series, as many as 71 88% of dermatomyositis and polymyositis patients, including those refractory to prednisone, improve with the addition of methotrexate [9,26 28]. One retrospective study suggested that methotrexate was more effective than azathioprine in males, patients with antisynthetase antibodies, and in those patients previously refractory to prednisone [28]. The therapeutic effect can be seen in a few weeks or months. A small (11 patients), unblinded, prospective, cross-over designed study compared prednisone plus azathioprine plus oral methotrexate to prednisone plus intravenous methotrexate in patients with IBM [10]. There was no clinically significant improvement in strength, although the serum creatine kinase levels decreased in most of the patients and there was no decline in strength over the 6- month treatment. However, a subsequent 48-month randomized, placebo-controlled trial of methotrexate in 44 patients with IBM did not demonstrate efficacy [19.. ]. Methotrexate is often preferred over azathioprine in patients with dermatomyositis and polymyositis because it is considered to have a more rapid benefit. We usually begin methotrexate orally at 7.5 mg/week given in three divided doses, 12 h apart. The dose is increased by 2.5 mg every 1 4 weeks up to 20 mg/week as tolerated and necessary. If there is no improvement after 1 month of 20 mg/week of oral methotrexate, we switch to weekly parenteral (intramuscularly or intravenously) methotrexate and increase the dose by 5 mg every 1 4 weeks up to 60 mg/week. In patients with severe weakness or myocarditis, we have initiated treatment at higher parenteral doses (e.g mg intramuscularly per week) rather than beginning at lower enteral doses. The major side effects of methotrexate are alopecia, stomatitis, pulmonary fibrosis, teratogenicity, oncogenicity, risk of infection, bone marrow suppression, renal and liver toxicity. Methotrexate doses over 50 mg/week require leukovorin rescue, although we rarely use such high doses. Nevertheless, concurrent folic acid supplementation is prescribed for all patients on methotrexate to reduce potential side effects. Because methotrexate can cause pulmonary fibrosis we avoid its use in patients with myositis who already have the associated interstitial lung disease or Jo-1 antibodies. Baseline and periodic pulmonary function tests with diffusion capacities need to be checked in patients prior to starting methotrexate and yearly while on treatment.

4 572 Neuromuscular diseases: muscle Table 2. Immunosuppressive therapy for inflammatory myopathies Therapy Route Dose Side effects Monitor Prednisone p.o. 100 mg/day for 2 4 weeks, then 100 mg every other day; single a.m. dose Methylprednisone i.v. 1 g in 100 ml/normal saline over 1 2 h, daily or every other day for 3 6 doses Hypertension, fluid and weight gain, hyperglycemia, hypokalemia, cataracts, gastric irritation, osteoporosis, infection, aseptic femoral necrosis Arrhythmia, flushing, dysgeusia, anxiety, insomnia, fluid and weight gain, hyperglycemia, hypokalemia, infection Azathioprine p.o. 2 3 mg/kg/day; single a.m. dose Flu-like illness, hepatotoxicity, pancreatitis, leukopenia, macrocytosis, neoplasia, infection, teratogenicity Methotrexate p.o mg weekly, single or divided doses; 1 day a week dosing Mycophenolate mofetil i.v./i.m. p.o mg weekly; 1 day a week dosing Adults: g twice daily; no more than 1 g per day in adults with renal failure. Children: 600 mg/m 2 /dose twice daily Hepatotoxicity, pulmonary fibrosis, infection, neoplasia, infertility, leukopenia, alopecia, gastric irritation, stomatitis, teratogenicity Same as p.o. Bone marrow suppression, hypertension, diarrhea, tremor, nausea, vomiting, headache, sinusitis, cough, amblyopia, confusion, infections, neoplasia, teratogenicity Cyclophosphamide p.o mg/kg/day; single a.m. dose Bone marrow suppression, infertility, hemorrhagic cystitis, alopecia, infections, neoplasia, teratogenicity i.v. 1 g/m 2 Same as p.o. (although more severe), and nausea/vomiting, alopecia Chlorambucil p.o. 4 6 mg/day; single a.m. dose Bone marrow suppression, hepatotoxicity, neoplasia, Cyclosporine p.o. 4 6 mg/kg/day, split into two daily doses Tacrolimus p.o. Adults: mg/kg/day divided into 2 doses, 12 h apart. Children: mg/kg/day divided into 2 doses, 12 h apart Intravenous immunoglobulin i.v. 2 g/kg over 2 5 days; then every 4 8 weeks as needed infertility, teratogenicity, infection Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsuitism, tremor, gum hyperplasia, teratogenicity Nephrotoxicity, hypertension, infection, hepatotoxicity, hirsuitism, tremor, gum hyperplasia, teratogenicity Hypotension, arrhythmia, diaphoresis, flushing, nephrotoxicity, headache, aseptic meningitis, anaphylaxis, stroke p.o., orally; i.v., intravenously; i.m., intramuscularly. Modified from Amato and Barohn [1] with permission. Weight, blood pressure, serum glucose/potassium, cataract formation Heart rate, blood pressure, serum glucose/potassium Monthly blood count, liver enzymes while adjusting the dose then every 3 months Weekly liver enzymes, blood count while adjusting the dose and then monthly Same as p.o. Blood counts are performed weekly for 1 month, twice monthly for the 2nd and 3rd month, and then once a month for 1 year Monthly blood count, urinalysis Daily to weekly blood count, urinalysis Monthly blood count, liver enzymes Blood pressure, monthly cyclosporine level, creatinine/ blood urea nitrogen (BUN), liver enzymes Blood pressure, monthly tacrolimus level, creatinine/bun, liver enzymes Heart rate, blood pressure, creatinine/bun We monitor a complete blood count (CBC) and liver function tests aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubins, and g-glutamyl transpeptidase (GGT) every 1 2 weeks until the patient is on a stable dose of methotrexate, then once a month. It is important to check the GGT, as it is the most reliable indicator of hepatic dysfunction, because the AST and ALT are often elevated from muscle involvement. Azathioprine Retrospective studies suggest that azathioprine is effective in some patients with dermatomyositis and polymyositis [2,9,21]. Improvement on azathioprine was reported in 64% of dermatomyositis and polymyositis patients, although a complete response occurred in only 11% [9]. Not surprisingly, patients with a previously good response to prednisone were more likely than prednisone-refractory patients to improve with the addition of azathioprine. A prospective, double-blind study comparing azathioprine (2 mg/kg) in combination with prednisone to placebo plus prednisone reported no significant difference in objective improvement at 3 months [12]. In the open-label follow-up period, however, patients on the combination of azathioprine and prednisone did better and required lower doses of

5 Idiopathic inflammatory myopathies Amato and Griggs 573 prednisone than those patients taking prednisone alone [29]. The major draw-back of azathioprine is that it often takes 6 months or longer to be effective. We start azathioprine at a dose of 50 mg/day in adults and gradually increase every 1 2 weeks to a total dose of 2 3 mg/kg/day. A systemic reaction characterized by fever, abdominal pain, nausea, vomiting, and anorexia occurs in 12% of patients requiring discontinuation of the drug [30]. This systemic reaction generally occurs within the first few weeks of therapy and resolves within a few days of discontinuing the azathioprine. Rechallenge with azathioprine usually results in the recurrence of the systemic reaction. Other major complications of azathioprine are bone marrow suppression, hepatic toxicity, pancreatitis, teratogenicity, oncogenicity, and risk of infection. Allopurinol should be avoided, because combination with azathioprine increases the risk of bone marrow and liver toxicity. We monitor CBC, liver function tests including GGT every 1 2 weeks until the patient is on a stable dose of azathioprine, and then once a month. Intravenous immunoglobulin Several retrospective and uncontrolled studies have suggested that IVIG is beneficial in dermatomyositis and polymyositis [31 35,36. ]. There have been no prospective, double-blind, placebo-controlled trials of IVIG in polymyositis. In a landmark study, Dalakas et al. [11] demonstrated the efficacy of IVIG in a prospective, double-blind, placebo-controlled studied of 15 patients with dermatomyositis. Repeat biopsies in five of the responsive patients revealed an increase in muscle fiber diameter, an increase in the number and decrease in the diameter of capillaries, a decrease in complement on capillaries, and a reduction in the expression of intercellular adhesion molecule 1 and major histocompatibility class 1 antigens supporting the objective clinical benefit. This was the first and remains the only doubleblind, placebo-controlled trial of any agent showing benefit in patients with any form of myositis. Nonblinded, uncontrolled studies of IVIG in IBM have been associated with mixed results [37,38]. Three prospective, double-blind, placebo-controlled studies of IVIG, however, demonstrated no significant improvement [14 16]. Given that IVIG is the only agent with demonstrated efficacy in double-blind, placebo-controlled trials, an argument can be made for IVIG being used as the first of the second-line agents before methotrexate or azathioprine. Moreover, in certain patients (e.g. those with interstitial lung disease, myocarditis, or other lifethreatening complications), we use IVIG early on, often in combination with prednisone and methotrexate or azathioprine. In our experience, IVIG works faster than azathioprine and perhaps methotrexate and may produce improvement while these later agents are being introduced. In patients with dermatomyositis, we initiate IVIG (2 g/ kg) slowly over 2 5 days and repeat infusions at monthly intervals for at least 3 months. Patients should have baseline renal function checked, especially those with diabetes mellitus, because of a risk of IVIG-induced renal failure. Headaches, myalgias, fever, chills, nausea, vomiting, flushing and hypotension are common and occur in as many as half the patients and are usually related to the rate of infusion. Lowering the rate of infusion can help alleviate these symptoms and signs. Rash, aseptic meningitis, and stroke can occur. Third-line treatments In patients with DM or PM refractory to corticosteroids and the second-line agents, several third-line agents may be tried. These agents are either more toxic than corticosteroids and second-line agents or have not been as extensively used in the treatment of inflammatory myopathies and therefore are recommended only in refractory patients. Cyclophosphamide Some studies have reported benefit in individual patients with dermatomyositis or polymyositis with oral and intravenous cyclophosphamide [21,39]. However, other studies have shown little improvement but increased morbidity with cyclophosphamide [40,41]. Cyclophosphamide should be reserved for patients refractory to prednisone, methotrexate, azathioprine, and IVIG. Cyclophosphamide is given orally at a dose of mg/kg/day or intravenously at a dose of 1 g/m 2 / month for patients. The major side effects are gastrointestinal symptoms, bone marrow toxicity, alopecia, hemorrhagic cystitis, teratogenicity, sterilization, and increased risk of infections and secondary malignancies. High fluid intake must be maintained to reduce the risk of hemorrhagic cystitis. Urinalysis and CBCs need to be followed closely (every 1 2 weeks at the onset of therapy and then at least monthly). Chlorambucil There are a few reports of polymyositis and dermatomyositis being treated with this medication [26,42,43]. Five dermatomyositis patients previously refractory to prednisone, azathioprine, and methotrexate improved within 4 6 weeks of starting oral chlorambucil (4 mg/ day) [42]. Four patients were able to stop the chlorambucil and corticosteroids after months with remission of their dermatomyositis. Chlorambucil

6 574 Neuromuscular diseases: muscle in combination with methotrexate and prednisone may also be effective in refractory polymyositis and dermatomyositis [26,43]. The risks of secondary malignancies, liver and bone marrow toxicity are presumably increased on chlorambucil and all alkylating agents. CBCs and liver function tests need to be assessed frequently. Other significant side effects include a hypersensitivity reaction with severe rash (Stevens Johnson syndrome), gastrointestinal disturbance, infection, teratogenicity, and liver toxicity. Fludarabine Fludarabine is an adenine analog used for the treatment of hematologic malignancies. A pilot study of fludarabine 20 mg/m 2 /month for 6 months in 16 patients with refractory dermatomyositis and polymyositis was associated with improvement in four patients and no change in seven, while the drug had to be withdrawn in five secondary to side effects or worsening of their condition [44]. Cyclosporine and tacrolimus There are several small series which report that cyclosporine ( mg/kg/day) is efficacious in treatment of dermatomyositis and polymyositis, including childhood dermatomyositis [45 50]. Improvement in strength is noticeable within 2 6 weeks, and prednisone can be decreased or discontinued in the majority of patients. Tacrolimus, an immunophilin similar to cyclosporine, also has been effective in a small number of refractory polymyositis and dermatomyositis patients [51]. Side effects of cyclosporine and tacrolimus are renal toxicity, hypertension, electrolyte imbalance, gastrointestinal upset, hypertrichosis, gingival hyperplasia, oncogenicity, tremor, and risk of infection. We start cyclosporine at a dose of mg/kg/day in two divided doses and gradually increase to 6.0 mg/kg/ day as necessary. The cyclosporine dose should initially be titrated to maintain trough serum cyclosporine levels of ng/ml. Blood pressure, electrolytes and renal function, and trough cyclosporine levels need to be monitored periodically. The dose of tacrolimus is mg/kg/day in two divided doses. Mycophenolate mofetil Mycophenolate mofetil selectively blocks purine synthesis of T- and B-cell lymphocytes thereby inhibiting their proliferation. There are a few reports of individual or small series of patients with dermatomyositis and polymyositis who responded to mycophenolate mofetil [52 54]. We initiate treatment in adults at 1.0 g by mouth twice a day. The dose can be increased up to 1.5 mg twice a day. In patients with renal failure, the dose should be no more than 1.0 g/day total. Side effects include diarrhea, nausea, vomiting, headache, bone marrow suppression, hypertension, tremor, infection, neoplasia, teratogenicity. Tumor-necrosis factor-a blockers Etanercept and infliximab are monoclonal antibodies that block the effect of tumor necrosis factor-a, a cytokine with a possible role in the pathogenesis of muscle destruction in dermatomyositis and polymyositis. Both etanercept and infliximab have been reported to be effective in refractory dermatomyositis and polymyositis in several abstracts [55 59]. Prospective trials assessing the efficacy of these agents are currently underway or planned. Conclusion Dermatomyositis, polymyositis, and IBM are clinically, histologically, and pathogenically distinct categories of idiopathic inflammatory myopathy. Dermatomyositis and polymyositis are responsive to immunosuppressive therapy, in contrast to IBM, which is generally refractory to therapy. Prospective, double-blind, placebo-controlled trials are necessary to determine prognostic features and the best treatment options for these myopathies. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as:. of special interest.. of outstanding interest 1 Amato AA, Barohn RJ. Idiopathic inflammatory myopathies. Neurol Clin 1997; 15: Amato AA, Gronseth GS, Jackson CE, et al. Inclusion body myositis: clinical and pathological boundaries. Ann Neurol 1996; 40: Dalakas MC. Polymyositis, dermatomyositis, and inclusion body myositis. N Engl J Med 1991; 325: Dalakas MC. Progress in inflammatory myopathies: good but not good enough. J Neurol Neurosurg Psychiatry 2001; 70: Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995; 38: Lotz BP, Engel AG, Nishino H, et al. Inclusion body myositis: observations in 40 patients. Brain 1989; 112: Mastaglia FL, Garlep MJ, Philips BA, Zilco PJ. Inflammatory myopathies: clinical, diagnostic, and therapeutic aspects. Muscle Nerve 2003; 27: This invited review presents an up-to-date treatise on clinical features, pathogenic basis, and treatment of dermatomyositis, polymyositis and IBM. 8. Oddis CV. Idiopathic inflammatory myopathy: management and prognosis. Rheum Dis Clin North Am 2002; 28: A rheumatologist s perspective on treatment of inflammatory myopathies. 9 Joffe MM, Love LA, Leff RL. Drug therapy of idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy. Am J Med 1993; 94: Leff RL, Miller FW, Hicks J, et al. The treatment of inclusion body myositis: a retrospective review and a randomized, prospective trial of immunosuppressive therapy. Medicine 1993; 72: Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med 1993; 329: Bunch TW, Worthington JW, Combs JJ, et al. Azathioprine with prednisone for polymyositis. Ann Intern Med 1980; 92:

7 Idiopathic inflammatory myopathies Amato and Griggs Miller FW, Leitman SF, Cronin ME, et al. Controlled trial of plasma exchange and leukopheresis in polymyositis and dermatomyositis. N Eng J Med 1992; 326: Dalakas MC, Sonies B, Dambrosia JM, et al. Treatment of inclusion body myositis with IVIg: a double-blind, placebo-controlled study. Neurology 1997; 8: Walter MC, Lochmuller H, Toepferm, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebocontrolled study. J Neurol 2000; 247: Dalakas MC, Koffman B, Fuji M, et al. A controlled trial of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 2001; 56: Muscle Study Group. A randomized trial of binf1a (Avonex) in patients with inclusion body myositis (IBM). Neurology 2001; 57: Rutkove SB, Parker RA, Nardin RA, et al. A pilot randomized trial of oxandrolone in inclusion body myositis. Neurology 2002; 58: This was a double-blind, placebo-controlled, cross-over study of oxandrolone for 3 months in 19 patients with IBM. A trend towards improvement was demonstrated in the maximum voluntary isometric contraction testing MVICT scores with oxandrolone and in the number of stairs climbed, but no significant differences were noted in other outcome measures Badsrising UA, Maat-Schieman MLC, Ferrari MD, et al. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann Neurol 2002; 51: This was a 48-month randomized, placebo-controlled trial of methotrexate (up to 20 mg/week orally) in 44 patients with IBM. No treatment-associated improvement was seen. 20 Barohn RJ. The therapeutic dilemma of inclusion body myositis. Neurology 1997; 48: Tymms KE, Webb J. Dermatomyositis and other connective tissue diseases: a review of 105 cases. J Rheumatol 1985; 12: Laxer RM, Stein LD, Petty RE. Intravenous pulse methylprednisolone treatment of juvenile dermatomyositis. Arthritis Rheum 1987; 30: Barohn RJ, Amato AA, Sahenk Z, et al. Inclusion body myositis: explanation for poor response to therapy. Neurology 1995; 45: Rose M, McDermott M, Thornton CA, et al. Prospective natural history study of inclusion body myositis: implications for clinical trials. Neurology 2001; 57: Saag KG, Emkey R, Schnitzer TJ, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998; 339: Cagnoli M, Marchesoni A, Tosi S. Combined steroid, methotrexate, and chlorambucil therapy for steroid resistant dermatomyositis. Clin Exp Rheumatol 1991; 9: Giannini M, Callen JP. Treatment of dermatomyositis with methotrexate and prednisone. Arch Dermatol 1979; 115: Metzger AL, Bohan A, Goldberg LS, et al. Polymyositis and dermatomyositis: combined methotrexate and corticosteroid therapy. Ann Intern Med 1974; 81: Bunch TW. Prednisone and azathioprine for polymyositis: long-term followup. Arthritis Rheum 1981; 24: Kissel JT, Levy RJ, Mendell JR, Griggs RC. Azathioprine toxicity in neuromuscular disease. Neurology 1986; 36: Cherin P, Herson S, Wechsler B, et al. Efficacy of intravenous globulin therapy in chronic refractory polymyositis and dermatomyositis: an open study with 20 adult patients. Am J Med 1991; 91: Hanslik T, Jaccard A, Guillon JM, et al. Polymyositis and chronic graft-versushost disease: efficacy of intravenous gammaglobulin. J Am Acad Dermatol 1993; 28: Jann S, Beretta S, Moggio M, et al. High-dose intravenous immunoglobulin in polymyositis resistant to treatment. J Neurol Neurosurg Psychiatry 1992; 55: Lang BA, Laxer RM, Murphy G, et al. Treatment of dermatomyositis with intravenous immunoglobulin. Am J Med 1991; 91: Al-Mayouf SM, Laxer RM, Schneider R, et al. Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety. J Rheumatol 2000; 27: Cherin P, Pelletier S, Teixeira A, et al. Results and long-term follow up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002; 46: Thirty-five patients with refractory polymyositis were treated with IVIG 2 g/kg/ month for 4 6 months in an open-label fashion. Clinical improvement, lower creatine kinase levels, and prednisone dose reduction by 50% or more were seen in 25/35 patients. 37 Soueidan SA, Dalakas MC. Treatment of inclusion body myositis with highdose intravenous immunoglobulin. Neurology 1993; 43: Amato AA, Barohn RJ, Jackson CE, et al. Inclusion body myositis: treatment with intravenous immunoglobulin. Neurology 1994; 44: Leroy JP, Drosos AA, Yiannopoulos DI, et al. Intravenous pulse cyclophosphamide therapy in myositis and Sjögren s syndrome. Arthritis Rheum 1990; 33: Cronin ME, Miller FW, Hicks JE, et al. The failure of intravenous cyclophosphamide therapy in refractory idiopathic inflammatory myopathy. J Rheumatol 1989; 16: Fries JF, Sharp GC, McDevitt HO, et al. Cyclophosphamide therapy in systemic lupus erythematosus and polymyositis. Arthritis Rheum 1973; 16: Sinoway PA, Callen JP. Chlorambucil: an effective corticosteroid-sparing agent for patients with recalcitrant dermatomyositis. Arthritis Rheum 1993; 36: Wallace DJ, Metzger AL, White KK. Combination immunosuppressive treatment of steroid-resistant dermatomyositis/polymyositis. Arthritis Rheum 1985; 28: Adams EM, Pucino F, Yarboro C, et al. A pilot study: use of fludarabine for refractory dermatomyositis and polymyositis, and examination of end-point measures. J Rheumatol 1999; 26: Correia O, Polonia J, Nunes JP, et al. Severe acute form of adult dermatomyositis treated with cyclosporine. Int J Dermatol 1992; 31: Heckmatt J, Hasson N, Saunders C, et al. Cyclosporine in juvenile dermatomyositis. Lancet 1989; 1: Qushmaq KA, Chalmers A, Esdaile JM. Cyclosporine A in the treatment of refractory adult polymyositis/dermatomyositis: population based experience in 6 patients and literature review. J Rheumatol 2000; 27: Lueck CJ, Trend P, Swash M. Cyclosporine in the management of polymyositis and dermatomyositis. J Neurol Neurosurg Psychiatry 1991; 54: Mehregan AL, Su WPD. Cyclosporine treatment for dermatomyositis/ polymyositis. Cutis 1993; 51: Pistoia V, Buoncompagni A, Scribanis R, et al. Cyclosporin A in the treatment of juvenile chronic arthritis and childhood polymyositis dermatomyositis: results of a preliminary study. Clin Exp Rheumatol 1993; 11: Oddis CV, Sciurba FC, Elmagd KA, Starzl TE. Tacrolimus in refractory polymyositis with interstitial lung disease. Lancet 1999; 353: Gelber AC, Nousari HC, Wigley FM. Mycophenolate mofetil in the treatment of severe skin manifestations: a series of four cases. J Rheumatol 2000; 27: Schneider C, Gold R, Schafers M, Toyka KV. Mycophenolate mofetil in the therapy of refractory polymyositis. Muscle Nerve 2002; 25: Chaudhry V, Cornblath DR, Griffin JW, et al. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular disease. Neurology 2001; 56: Hengstman G, Van Den Hoogen F, Van Den Engelen B, et al. Anti-TNF blockade with Infliximab in polymyositis and dermatomyositis. Arthritis Rheum 2000; 43 (Suppl 1):S Maillard SM, Wilkinson NMR, Beresford MW, et al. The treatment of persistent severe idiopathic inflammatory myositis with anti-tnf therapy. Ann Rheum Dis 2002; 61 (Suppl 1):S Miller ML, Mendez E, Klein-Gitelman MS, Pachman LM. Experience with etanercept in chronic juvenile dermatomyositis (JDM) [abstract]. Arthritis Rheum 2000; 43: Nzeusseau A, Durez P, Houssain FA, Devogelaer JP. Successful use of Infliximab in a case of refractory juvenile dermatomyositis. Arthritis Rheum 2001; 44:S Saadeh CK. Etanercept is effective in the treatment of polymyositis/ dermatomyositis which is refractory to conventional therapy including corticosteroids and other disease modifying agents. Arthritis Rheum 2000; 43 (Suppl 1):S193